Iontophoretic Drug Delivery Device and Reservoir and Method of Making Same

ABSTRACT

Abstract of Disclosure 
     A reservoir electrode assembly of the present invention for an iontophoretic drug delivery device includes an electrode and a hydrophilic reservoir situated in electrically conductive relation to the electrode.  The hydrophilic reservoir is formed from a bibulous hydrophilic cross-linked polymeric material having a first surface and a second surface that is adhesively adherent to the electrode.  The first surface of the polymeric material is releasably adhesively adherent when applied to an area of a patient&#39;s skin.  The polymeric material has a cohesive strength forms an adhesive bond with a bond strength between the second surface of the polymeric material to the electrode that is greater than the cohesive strength of the polymeric material.  Additionally, an adhesive bond strength of the first surface of the polymeric material to the applied area of the patient is less than the cohesive strength of the polymeric material so that upon removal of the reservoir assembly of the invention from the applied area of the patient, substantially no polymeric material remains on the applied area and the hydrophilic reservoir remains substantially intact and adhesively adherent to the electrode.

Cross Reference To Related Applications

[0001] This application is a continuation application claiming priorityunder 35 U.S.C. § 120 from Application Serial No. 09/328,329 whichissued into U. S. Patent No. 6,377,847 on April 23, 2002, that is acontinuation-in-part of Application No. 08/533,979 filed September 26,1995, now abandoned, which is a continuation-in-part of Application No.08/129,222 filed September 30, 1993, now abandoned.

Background of Invention

[0002] The present invention generally relates to iontophoretic systemsfor delivering medicaments such as therapeutic drugs and medicines topatients transdermally, i.e., through the skin, and more specificallyrelates to a stable iontophoretic drug delivery device and a reservoirfor use in the same. In addition, the present invention relates to amethod for making a stable iontophoretic drug delivery device with longshelf life and the reservoir for use in such a device.

[0003] Transdermal drug delivery systems have, in recent years, becomean increasingly important means of administering drugs. Such systemsoffer advantages clearly not achievable by other modes of administrationsuch as avoiding introduction of the drug through the gastro-intestinaltract or punctures in the skin to name a few.

[0004] Presently, there are two types of transdermal drug deliverysystems, i.e., "Passive" and "Active." Passive systems deliver drugthrough the skin of the user unaided, an example of which would involvethe application of a topical anesthetic to provide localized relief, asdisclosed in U.S. Patent No. 3,814,095 (Lubens). Active systems on theother hand deliver drug through the skin of the user, such as a patient,using iontophoresis, which according to Stedman's Medical Dictionary, isdefined as "the introduction into the tissues, by means of an electriccurrent, of the ions of a chosen medicament."

[0005] Conventional iontophoretic devices, such as those described inU.S. Patent Nos. 4,820,263 (Spevak et al.), 4,927,408 (Haak et al.) and5,084,008 (Phipps), the disclosures of which are hereby incorporated byreference, for delivering a drug or medicine transdermally throughiontophoresis, basically consist of two electrodes -- an anode and acathode. Usually, electric current is driven from an external supplyinto the skin at the anode, and back out at the cathode. Accordingly,there has been considerable interest in iontophoresis to performdelivery of drugs for a variety of purposes. Two such examples, involvethe use of Novocaine™, which is usually injected prior to dental work torelieve pain, and Lidocaine™, which is usually applied as a topical,local anesthetic.

[0006] Such prior devices have prior hereto not been pre-loaded andself-adhering, e.g., they have typically utilized an absorbent pad orporous solid sheet that can be filled with drug solution as the drugreservoir. These absorbent pads or porous sheets have three majordisadvantages. First, they must be filled with the drug solution afterremoval from the package since these pads or porous sheets do not holdthe drug solution as the solution is subject to removal and leakageunder pressure or flexure. In addition, even after the inconvenientaddition of the drug solution and after removal from the package, theabsorbent pad or porous sheet reservoir remain subject to leakage andsmearing of the drug solution due to pressure or flexure upon the skin.Furthermore, absorbent pads or porous solid sheets cannot provide theelectrical continuity to complete intimate contact since they lackadhesiveness and flexibility with the skin and its contours.

[0007] In addition, prior drug reservoirs have included pastes andunformed viscous semi-solid gels such as for example agar that have bothsolid and liquid characteristics as described, for example, in U.S.Patent No. 4,383,529 (Webster), the disclosure of which is herebyincorporated by reference.

[0008] Powers et al., U.S. Patent No. 4,886,277, although suggestingthat Lidocaine could be incorporated into the reservoir, fails to solvethe resulting problem associated with compatibility with adjacentmaterials such as conductive layers. Accordingly, such a device wouldfail to provide sufficient stability for extended shelf life, i.e., morethan one year.

[0009] However, several disadvantages and limitations have beenassociated with the use of such devices, including handleability andloadability. For example, the semi-solid agar reservoir disclosed inWebster flows under shear or stress. Furthermore, this disclosedreservoir may melt upon exposure to modest elevated temperatures. Theagar is unstable, spontaneously releasing aqueous solution.

[0010] Thus, there has been a need for an iontophoretic drug deliverydevice and a reservoir for use in the same, as well as a method formaking the reservoir, which would eliminate the problems and limitationsassociated with the prior devices discussed above, most significant ofthe problems being associated with stability, handleability, loadabilityand electrocontinuity of the reservoir, including chemical and thermalstability of the reservoir and the electrode.

Summary of Invention

[0011] A reservoir electrode assembly of the present invention for aniontophoretic drug delivery device includes an electrode and ahydrophilic reservoir situated in electrically conductive relation tothe electrode. The hydrophilic reservoir is formed from a bibuloushydrophilic cross-linked polymeric material having a first surface and asecond surface that is adhesively adherent to the electrode. The firstsurface of the polymeric material is releasably adhesively adherent whenapplied to an area of a patient's skin. The polymeric material has acohesive strength forms an adhesive bond with a bond strength betweenthe second surface of the polymeric material to the electrode that isgreater than the cohesive strength of the polymeric material.Additionally, an adhesive bond strength of the first surface of thepolymeric material to the applied area of the patient is less than thecohesive strength of the polymeric material so that upon removal of thereservoir assembly of the invention from the applied area of thepatient, substantially no polymeric material remains on the applied areaand the hydrophilic reservoir remains substantially intact andadhesively adherent to the electrode.

[0012] The reservoir electrode of the present invention providessolutions for several problems seen with available iontophoreticreservoir electrodes. The reservoir electrode of the invention, by beingadherent to the skin of the patient minimizes current pathwayconcentrations that often result in irritation and burning caused byincomplete contact of the reservoir electrode assembly to the patient'sskin. Because the adhesive bond of the electrode to the patient's skinis less than the cohesive strength of the polymeric material used forthe reservoir, substantially no residue from the reservoir material isleft behind on the patient's skin. Additionally, since the polymericreservoir material forms an adhesive bond with the electrode, there isintimate and effective electrical contact between the electrical circuitand the polymeric reservoir material. The reservoir electrode assemblyof the invention can be physically smaller than most currently availableelectrode assemblies because the entire polymeric reservoir ishydrophilic and is utilized to contain drugs and electrolytes. Manycurrent electrode assemblies require hydrophobic polymeric materials toachieve an adhesive tack and another hydrophilic material to retain theaqueous drug and electrolyte used for the iontophoretic delivery. When ahydrophobic and a hydrophilic component are used to form a reservoir, asin the currently available materials, some partitioning of themedicament may occur or there may be some binding of the active compoundwith the hydrophobic material that reduces the availability of themedicament for delivery. These effects are not seen with the hydrophilicreservoir of the invention.

[0013] In contrast to the prior devices discussed above, it has beenfound that a iontophoretic drug delivery device particularly suited foruse to deliver at least one medicament, particularly in a high doseefficiency, can be constructed in accordance with the present inventionby the incorporation of an aqueous swollen cross linked water solublepolymeric drug delivery reservoir adhesively coupled to the electrodesuch that the adhesive strength of the electrode material is greaterthan the cohesive strength of the reservoir material. In addition, thedevice of the present invention can easily fit over any contour of thebody and provide excellent electrocoupling with the electrode and theskin, while still being capable of flexing and adhering to the skin.Also the device of the present invention can be applied over a range oftemperatures and is stable for over one year at controlled roomtemperature to provide a commercially advantageous shelf-life.

[0014] The iontophoretic drug delivery device of the present inventionfor delivering at least one medicament to an applied area of a patient,such as the skin, mucous membrane and the like, including electrodeassembly means for driving a medication into the applied area of thepatient to be absorbed by the body of the patient, the electrode includean electrode material, and a covalently cross linked hydrophilicreservoir situated in electrically conductive relation to the electrodeassembly means, with the reservoir including an aqueous swollen crosslinked water soluble polymer material having an adhesive strength to theelectrode material, an adhesive strength to the applied area and acohesive strength to itself, with the reservoir containing at least onemedicament, wherein the adhesive strength of the polymer material to theelectrode material is greater than the cohesive strength of the polymermaterial and the adhesive strength of the polymer material to theapplied area is less than the cohesive strength of the polymer materialso that upon removal of the device from the applied area little if anypolymer material remains on the applied area, while maintaining thereservoir intact and in intimate contact with the electrode material.

[0015] In the preferred embodiment, the device of the invention furtherincludes a structurally reinforcing member situated within the reservoirincluding the aqueous swollen cross linked water soluble polymer, withthe structurally reinforcing member having an open area that is thin andof sufficient voidage so as not to impede the flow of ions. In addition,the structurally reinforcing member is a thermoplastic polymeric scrimand the aqueous swollen cross linked water soluble polymer is crosslinkable by high energy irradiation with the scrim being wettable enoughand with open area of greater than 40% to insure phase continuity thoughthe scrim, along with sufficient adhesion to contribute strength to theaqueous cross linked polymeric reservoir. Also, the aqueous swollencross linked water soluble polymer is selected from the group includingpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylamide. The at least one medicamentincludes Lidocaine and the reservoir also includes a vasoconstrictor,stabilizers and glycerin. Further, the reservoir further includesadditives and conductive salts, with the additives selected from thegroup including glycerin, propylene glycol, polyethylene glycol andpreservatives.

[0016] The reservoir of the present invention for use in aniontophoretic drug delivery device having an electrode assemblyincluding an electrically conductive electrode material for deliveringat least one medicament through an applied area of a patient, such asthe skin, mucous membrane and the like, includes a layer of a aqueousswollen cross linked water soluble polymer material capable of havingelectrocontinuity with the electrode assembly, with the aqueous swollencross linked water soluble polymer material having sufficient adhesivetack including the at least one medicament for delivery through anapplied area of a patient, such as the skin, mucous membrane and thelike, and the aqueous swollen cross linked water soluble polymermaterial having an adhesive strength to the electrode material greaterthan the cohesive strength of the polymer material, and the cohesivestrength being greater than an adhesive strength to the applied area.

[0017] In the preferred embodiment, the reservoir also includes astructurally reinforcing member situated within the layer of aqueousswollen cross linked water soluble polymer material, with thestructurally reinforcing member having approximately 40% porosity so asnot to impede the flow of ions, with the structurally reinforcing memberbeing a wettable, scrim of a aqueous insoluble thermoplastic polymericmaterial and the aqueous swollen cross linked water soluble polymermaterial is cross linked by high energy irradiation. Also, aqueousswollen cross linked water soluble polymer is selected from the groupincluding polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyacrylamide and polyethylene glycol. In addition, the at least onemedicament includes Lidocaine and the aqueous swollen cross linked watersoluble polymer material includes a vasoconstrictor, stabilizers andglycerin. Further, the reservoir includes additives and conductivesalts, with the additives selected from the group including glycerin,propylene glycol and polyethylene glycol and preservatives.

[0018] The method of making a reservoir for an iontophoretic drugdelivery device of the present invention includes the steps of providinga structurally reinforcing member, coating the reinforcing member with aviscous water soluble polymer solution on both sides of the structurallyreinforcing member such that the polymer solution penetrates the openarea, wets the reinforcing member, and cross linking the layer by highenergy irradiation, with the cross-linked layer of polymer having anadhesive strength to an electrode material greater than a cohesivestrength of the polymer, and the cohesive strength being greater than anadhesive strength to an applied area.

[0019] In the preferred embodiment of the method, the step of coatingincludes the steps of applying a layer of the viscous solution to oneside of the reinforcing member, applying a layer of the viscous solutionto one side of a release liner and laminating the release liner and thereinforcing material together such that both surfaces of the reinforcingmember are coated with the viscous solution. In addition, the viscoussolution is applied to the reinforcing member and the release liner to athickness of about Ca. 5 mil to 70 mil. The method also includes thestep of applying final release liners to the remaining exposed viscoussolution coated surfaces of the reinforcing member to form a laminateand cross linking the viscous solution. Also, the method includes thesteps of replacing one of the final release liners with an electrode inflexible sheet form, and adding at least one medicament to the crosslinked water soluble polymer, with the at least one medicament includesLidocaine and the cross linked water soluble polymer includes avasoconstrictor, stabilizers, glycerin and preservative. Further, themethod includes the of cutting the laminate into a suitable shape andarea and laminating it to a conductive metal for use in an iontophoreticdrug delivery device.

Brief Description of Drawings

[0020] The various features, objects, benefits, and advantages of thepresent invention will become more apparent upon reading the followingdetailed description of the preferred embodiment along with the appendedclaims in conjunction with the drawings, wherein like reference numeralsidentify corresponding components, and:

[0021]Figure 1 is a schematic view of the iontophoretic drug deliverydevice of the present invention illustrating placement of the device ona user;

[0022]Figure 2 is a cross sectional view of the device of the presentinvention;

[0023] Figures 3A, 313, 3C and 3D are schematic views of the varioussteps of the method for making the reservoir of the present invention;

[0024]Figure 4 is a logic flow diagram depicting the various steps ofthe method for making the reservoir of the present invention;

[0025]Figure 5 is a cross-sectional view of the reservoir electrodeassembly of the invention;

[0026]Figure 6 is a schematic perspective view of the reservoir of theinvention from Fig. 5;

[0027]Figure 7 is a schematic cross-sectional view of the coating andcross-linking of the web for forming the PVP reservoir; and

[0028]Figure 8 is a schematic top plan view of the web illustratingpunching out individual reservoir units.

Detailed Description

[0029] The iontophoretic drug delivery device of the present inventionis illustrated in Figures 1 and 2, and generally includes thedesignation 10. Referring to Figures 1 and 2, the device 10 of thepresent invention includes an electrode assembly 12, having at least oneelectrode and at least one reservoir, with the reservoir and electrodeheld or contained within a suitable structure 16, with a skin adhesive18. Also, as is well known in the art, a power source 19 is provided incircuit with the electrode assembly 12 for supplying a source ofelectrical current. It should be appreciated that a return electrode andreservoir may be combined into a single electrode assembly 12 orseparately provided as illustrated in Figure 1.

[0030] In the preferred embodiment, the device is divided or otherwiseseparated into two portions 20 and 22, with the electrode assembly 12including two electrodes 24 and 26. One portion 20 (first) includes theelectrode 24 and a reservoir 28, with the reservoir being situatedadjacent and coupled to the electrode 24 and holding at least onemedicament or drug 30, preferably in ionized or ionizable forms, to bedelivered iontophoretically. The other portion 22 (second) includes theelectrode 26 and a reservoir 32, with the reservoir being situatedadjacent to the electrode 26 and holding an electrolyte 34. Theparticular electrolyte is not essential to the present invention and ismerely a matter of choice. However, in this embodiment the electrolytemay include sodium chloride in an aqueous solution, matrix or the likeas explained in greater detail herein below.

[0031] A schematic diagram of the first portion 20 of the device 10 isillustrated in Figure 2. In this case, the medicament 30 to be deliveredthrough the skin is a cation and the reservoir 28 is connected to theelectrode 24, which acts as an anode. The return electrode 26 (cathode)may be constructed in the manner as the working electrode 24. If thedrug is an anion, then the drug containing reservoir would be connectedto the cathode and the return reservoir would be connected to the anode.

[0032] As is well known within the field, the device can be situated onthe area of the patient to which the medicament is to be applied (theapplied area) and a voltage impressed across the electrodes 24, 26 ofthe electrode assembly 12 to cause current to flow through the skin 60of the patient to drive the ionic medicament locally into the skin andthe tissue or to be absorbed systematically by the body of the patient.It should also be appreciated that the device of the present inventioncan be applied to other areas of the body such as mucous membranes andthe like depending upon the desired therapy and medicaments to bedelivered.

[0033] In order to transport the medicament through intact skin 60 atleast the reservoir 28 containing the medicament includes an aqueousswollen cross linked water soluble polymer, which for simplicity ishereinafter referred to as a cross linked water soluble polymer. Thecross linked water soluble polymer can be incorporated into thereservoir as a homogeneous solid cut or molded sheet 40 of suitableshape and area which can be attached to the electrode as illustrated inFigures 1 and 2. However, it should be appreciated that the reservoir 32(cathode) may also be made of the same material as the reservoir 28containing the medicament, i.e., to include the cross linked watersoluble polymer sheet 40 illustrated in Figures 3A-3D. Accordingly, thecross linked water soluble polymer sheet 40 containing either themedicament and/or the electrolyte serves as the reservoirs 28, 32 andthe electrical coupling to the skin while being able to conform to allcontours of the body. In addition, the reservoir may include additivesselected from the group including glycerin, propylene glycol,polyethylene glycol and conductive salts, as well as preservatives.

[0034] The particular cross linked water soluble polymer material may bemade from a variety of commercially available water soluble polymersknown to those skilled in the art as long as it is of low bioburden, iselectrically conductive, readily conforms to the contours of the body,is capable of being cross linked and can hold or otherwise retain thedrug solution under pressure and flexure.

[0035] Cross linked water soluble polymers are preferred reservoirs asthey provide a conformable interface with good electrical coupling andexcellent biocompatibility. Examples of such cross linked water solublepolymers are irradiated cross linked polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG),polyacrylamide and polyethylene glycol (PEG). The cross linked watersoluble polymer sheet 40 by nature of its preparation by irradiationcross linking is of low bioburden and is non toxic, non irritating andnon sensitizing to the skin. This is particularly assured by the factthat no chemical cross linking agents or organic solvents are requiredto synthesize the cross linked water soluble polymer material. It shouldbe appreciated, that the techniques of irradiation cross linking thewater soluble polymer material are well known in the art.

[0036] In the preferred embodiment, the cross linked water solublepolymer sheet 40 may include a netting or non-woven material 42 such asan inert and wetable polyethylene terphthalate (PET) material is theform of a scrim commercially available from Reemay, Inc. The scrimutilized for this application is preferably an open web, inert, waterinsoluble material that does not change the conductivity or ionic flowof the materials in the water, soluble polymer. In addition, the scrimis wetable and porous. The basis weight of the scrim being of a basisweight between Ca. 4 to 60 grams/square yard. Also, in this way, thecross linked water soluble polymer sheet 40 can be formed from asolution 44 of pre-mixes after dispersion and full solution, with thesolution then applied on both sides of the scrim 42 to a thickness ofCa. 5 mil to 40 mil and then cross linked by high energy irradiationsuch as for example, electron beam or gamma irradiation to form covalentcross links. The particular thickness of the cross linked water solublepolymer sheet may vary depending upon, e.g., the medicament to bedelivered, the applied area and the like, from a very thin sheet, i.e.,film, for high drug efficiency to a very thick sheet for minimization ofsensation when an electrical current is applied. However it should alsobe appreciated that suitable scrim materials may include inorganicmaterials such as ceramics and composites such as fiberglass.

[0037] As illustrated in Figures 3A, 313, 3C and 3D, and the flowdiagram illustrated in Figure 4, preferably the cross linked watersoluble polymer sheet 40 is formed by providing the release liner 46 andthe scrim 42, applying or otherwise coating a release liner or otherbacking material 46 with one-half of the viscous solution 44 of water 25soluble polymer to form a layer 44A (Figure 313) and coating orotherwise applying the other half of the viscous solution 44 to one sideof the scrim 42 to form a layer 44B (Figure 3C). The coated liner 46 isthen laminated to the coated scrim 42 such that the scrim has theviscous solution on both sides (Figure 3D). Next, a final liner or otherbacking material 48 is then applied to the exposed surface, with thecross linked water soluble polymer sheet 40 sandwiched between the tworelease liners 46, 48 to form a laminate 50, which in the preferredembodiment is then exposed to high energy irradiation to cross link thewater soluble polymer solution. In the alternative, to provide ease ofhandling, the final release liner 48 can be applied to the coated scrimprior to lamination with the coated liner 46.

[0038] The scrim 42 itself imparts structural support and mechanicalstrength to the final cross linked water soluble polymer sheet toprevent shearing. Thereafter, the laminate 50 can be easily handled andcut or otherwise formed into the desired shape for the particularreservoir 28, 32. In this way, the release liner 46 can be subsequentlyremoved and the exposed surface of the cross linked water solublepolymer adhered to the electrode 24, 26, or removed and the medicament30 added and the release liner replaced or adhered to the electrode.Also, the release liner 48 can remain until being removed forapplication of the device 10 to the applied area of the patient.

[0039] In the alternative, the release liner 48 (or 46) can be replacedby the electrode in the form of a thin metal sheet or polymer sheetcoated with a conductive ink or metal foil laminated to the polymericsheet such as for example as disclosed in co-pending application SerialNumber 08/012,168, the disclosure of which is hereby incorporated byreference. In this way, the reservoir can be coupled to the electrode inone step. It should also be appreciated that a conductive scrim may beincorporated into the reservoir with the scrim being placedasymmetrically within the reservoir by placing different thicknesses ofthe viscous solution ob each side of the scrim.

[0040] The use of an easily handled cross linked water soluble polymersheet as the 25 reservoir 28, 32 to replace a paste, semi-solid gel oran absorbent pad has many advantages over existing coupling reservoirs.The cross linked water soluble polymer is solid and shape retaining andit exhibits no leakage of medicament or electrolyte under flexure orapplied pressure. It is also drapeable and flexible and adhesive to theskin. This assures that the cross linked water soluble polymer maintainsthe required medicament and electrolyte concentration as well asreproducible delivery by its adherence and conformability to thecontours of the skin or other applied area.

[0041] Also, the adhesive strength of the gel and the electrode materialis greater than the cohesive strength of the gel material and thecohesive strength of the gel is greater than the adhesive strength ofthe gel to the applied area, e.g., skin of the patient. In this way, anintimate electrical contact between the electrode and the reservoir isachieved which insures electrical continuity (and uniformity) betweenthe interface of the electrode and 10 the gel during applications of hedevice to the applied area. Also, upon removal of the device, little, ifany, material remains on the applied area after removal of the device.

[0042] Due to its high water content, the cross linked water solublepolymer is highly conductive to ionic transport, yet in combination withthe scrim, it possesses sufficient mechanical strength for processingand use. Also, despite its high water content, the cross linked watersoluble polymer is a single phase solid solution which does not synereseliquid spontaneously or upon applied pressure or flexure.

[0043] The ability of the cross linked water soluble polymer to retainaqueous solution and its stability over extremes of ambient temperature,allow the iontophoretic drug delivery device 10 to be prepackaged andstored as a ready to use device, eliminating the need for loading a drugsolution after opening and assembly.

[0044] In addition, the various reservoirs 28, 32 formed from the crosslinked water soluble polymer sheet 40 are easily and stabably coupledwith the electrically conductive electrodes 14, 26 to form a highlyelectrically conductive electrode assembly 12. Also, because of thehandleability of the cross linked water soluble polymer, the medicamentcan either be added to the viscous water soluble polymer solution orsubsequently added after cross linking depending upon the applicationand/or the medicament to be administered.

[0045] As previously discussed, the two portions of the device 20, 22are placed over the applied area, i.e., the portion of the skin wherethe medicament is to be delivered such as the arm as illustrated inFigure 1 with other electrode 32, i.e., the return electrode, placed onthe skin 60 at an appropriate location relative to the first or workingelectrode 14.

[0046] Further, the cross linked water soluble polymer 40 in thepreferred embodiment of the present invention is self-adhering to theskin of the patient and therefore provides intimate contact for ionictransport. Accordingly, the cross linked water soluble polymer sheet 40contained in the drug reservoir 28 and used for the electrolytereservoir 32 may also act as an adhesive, eliminating the need in priordevices for an adhesive layer or the like.

[0047] The following formulations for the cross linked water solublepolymer sheet 40 were used in connection with the device of the presentinvention for the reservoirs in the iontophoretic delivery of a topicalanesthetic and a vasoconstrictor, with the device 10 including oneactive electrode 24 having a surface area between 2-10 cm2 and one tothree return electrodes 26 having a total surface area between 1-5 cm2.The electrode reservoir 28 was comprised of the following active andinert components to a thickness of between 10-50 mils by making aviscous stock solution containing the medicaments and the excipientsthat was 3 times more concentrated than the intended final formulation.The stock solution was then added to pre-existing sheets as one partsolution to two parts sheet (by weight) and allowed to diffuse andequilibrate in the sheets.

[0048] EXAMPLE 1 Active Components Inert Components Concentration Massper 2.5 cmsq (%, w/w) (mg) Lidocaine hydrochloride, U.S.P. 10.00 45.000Epinephrine Bitartrate 0.10 0.450 Glycerin, U.S.P. 10.00 45.000 Crosslinked polyvinyl pyrrolidone (PVP), U.S.P. 16.67 75.020 Sodiummetabisulphite, U.S.P. 0.05 0.230 EDTA disodium, U.S.P. 0.01 0.045Citric acid, U.S.P. 0.02 0.090 Water 63.15 450 Total 100.00 450.000

[0049] In the preferred embodiment, the Lidocaine is an anesthetic, theEpinephrine Bitartrate ("Epinephrine") is a vasoconstrictor, and thecomposition of PVP is 10% to 20%, preferably 15%, known as K-90F fromBASF Corp. However, it should be appreciated that the concentration ofthe PVP may vary from approximately 10% to 60% w/w. In addition, itshould be appreciated that L-Adrenaline can be substituted for theEpinephrine.

[0050] After cross-linking the gel material of Example 1 having 25% PVP,75% water and 1 % preservative PHENONIP manufactured NIPA Corporation byexposure to 2 Mrad (20 kGy) and loaded with drug and excipients, it wasfound that this gel material when applied to an electrode comprised ofsilver/silver chloride ink printed onto a polyester substrate, such thatthe surface resistance is less than 3 ohm per square, and the driedcoating is porous yielded an average adhesive strength greater than 40grams/inch which was on average greater than the cohesive strength (peelstrength) of the gel material as evident by gel material tearing apartupon peeling, which remained on the electrode surface. Despite thisrelatively low cohesive strength, it was still sufficiently greater thanthe adhesive strength to the skin as evident by little, if any, gelmaterial remaining on the skin upon removal of the reservoir.

[0051] In another, after cross-linking the gel material of Example 1having 25% PVP, 75% water and 1% preservative PHENONIP manufactured NIPACorporation by exposure to 1.5 Mrad (15 kGy) and loaded with drug andexcipients, it was found that this gel material when applied to anelectrode comprised of silver/silver chloride ink printed onto apolyester substrate, such that the surface resistance is less than 3 ohmper square, and the dried coating is porous yielded an average adhesivestrength greater than 60 grams/inch which was on average greater thanthe cohesive strength (peel strength) of the gel material as evident bygel material tearing apart upon peeling, which remained on the electrodesurface. Despite this relatively low cohesive strength, it was stillsufficiently greater than the adhesive strength to the skin as evidentby little, if any, gel material remaining on the skin upon removal ofthe reservoir.

[0052] EXAMPLE 2

[0053] Same as Example 1, however, Polyethylene oxide (PEO) NF wassubstituted for the PVP with the unloaded reservoir polymerconcentration being around 1% to 6%, preferably 5.0%, however, it shouldbe appreciated that the concentration of the PEO may varying fromapproximately 1-10% w/w depending upon its molecular weight.

[0054] Further, material remaining on the electrode is preferred asevidencing intimate contact between the electrode and the reservoir.

[0055] EXAMPLE 3

[0056] Same as Example 1, with polyvinyl alcohol (PVA) being substitutedfor the PVP, and the preferred unloaded reservoir polymer concentrationof the PVA varying from approximately 10-30% w/w.

[0057] EXAMPLE 4

[0058] Same as Example 1, with polyethylene glycol (PEG) beingsubstituted for the PVP, and the preferred unloaded reservoir polymerconcentration of the PEG varying from 25 approximately 20-60% w/w.

[0059] EXAMPLE 5

[0060] Same as Example 1, with the addition of about 5-20% glycerin,preferably 10%, to the reservoir to keep the aqueous drug solution formdiffusing into all other phases in contact with the reservoir which isdefined herein as a "synerisis inhibitor".

[0061] Each of the above applications involved the use of devices forthe delivery of Lidocaine and Epinephrine for short application times,i.e., less than 30 minutes.

[0062] Drug, medication, medicament and active compound have been usedherein to mean any ionicly charged pharmaceutical agent, such astherapeutic compounds, diagnostic agents and the like.

[0063] In addition, it should be appreciated that the device andreservoir of the present invention may be packaged in a nitrogen richenvironment as disclosed in co-pending application Serial Number08/316,741, the disclosure of which is hereby incorporated by reference.

[0064] Further, while the present invention has been described inconnection with iontophoresis, it should be appreciated that it may beused in connection with other principles of electroactive introduction,i.e., motive forces, such as electrophoresis which includes the movementof particles in an electric field toward one or other electric pole,anode, or cathode and electro-osmosis which includes the transport ofuncharged compounds due to the bulk flow of water induced by an electricfield. Also, it should be appreciated that the patient may includehumans as well as animals.

[0065] While the preferred embodiments of the present invention havebeen described so as to enable one skilled in the art to practice thedevice and method of the present invention, it is to be understood thatvariations and modifications may be employed without departing from theconcept and intent of the present invention as defined in the followingclaims. The preceding description is intended to be exemplary and shouldnot be used to limit the scope of the invention. The scope of theinvention should be determined only by reference to the followingclaims.

[0066] While this invention is satisfied by embodiments in manydifferent forms, there are shown in the drawings and herein described indetail, embodiments of the invention with the understanding that thepresent disclosure to be considered as exemplary of the principles ofthe present invention and is not intended to limit the scope of theinvention to the embodiments illustrated. The scope of the invention ismeasured by the appended claims and the equivalents.

[0067] Referring to Figs. 5-8, a reservoir electrode assembly 110 of thepresent invention for an iontophoretic drug delivery device includes anelectrode 112 and a hydrophilic reservoir 114 situated in electricallyconductive relation to electrode 112. Hydrophilic reservoir 114 isformed from a bibulous hydrophilic cross-linked polymeric material 116having a first surface 118 and a second surface 120 that is adhesivelyadherent to electrode 112. First surface 118 of polymeric material 116is releasably adhesively adherent when applied to an area 122 of apatient's skin. Polymeric material 116 has a cohesive strength and formsan adhesive bond 124 with a bond strength between second surface 120 ofthe polymeric material to electrode 112 that is greater than thecohesive strength of polymeric material 116. Additionally, an adhesivebond strength of first surface 118 of polymeric 116 material to appliedarea 122 of the patient is less than the cohesive strength of polymericmaterial 116 so too that upon removal of reservoir assembly 110 of theinvention from the applied area of the patient, substantially nopolymeric material 116 remains on applied area 122 and hydrophilicreservoir 114 remains substantially intact and adhesively adherent toelectrode 112.

[0068] Adverting to Fig. 6, reservoir electrode assembly 110 preferablyincludes a reinforcement 126 to provide two-dimensional stability,indicated by reference characters x and y, to polymeric material 116 andallow a swelling of polymeric material 116 in a third dimension z.Reinforcement 126 may be formed from a woven material or a nonwovenmaterial. Preferably, reinforcement 126 is formed from a non-wovenmaterial with a basis weight about ten to about thirty grams per squaremeter. Reinforcement 126 is preferably disposed in a layer 128substantially intermediate first surface 118 and said second surface 120of bibulous hydrophilic polymeric material 116 so that when polymericmaterial 116 imbibes an aqueous solution, swelling of polymeric material116 is substantially limited to increasing a distance "d" between firstsurface 118 and second surface 120. Preferably, first surface 118 andsecond surface 120 are substantially parallel to each other. Suitablenon-woven materials are available from Reemay as a spun-bondedpoly(ethyleneterephthalate) 2004 (PET) with a basis weight of about 14grams per square meter. Other materials with other basis weights may bepreferred for particular applications and are considered within thescope of this disclosure.

[0069] A preferred material for forming hydrophilic reservoir 114 ispoly(vinylpyrollidone) ( PVP) with a number average molecular weightgreater than about 360,000 daltons. A suitable PVP is available fromBASF, NJ as PVP K-90F. When this material is prepared as a concentratedaqueous solution it forms a viscous syrup which is preferably applied toboth sides of the reinforcement 126, placed between two release webs toa thickness of about of about 40 mils and subjected to ionizingradiation sufficient to cross-link the PVP sufficiently to substantiallybe shape retaining, flexible and having a degree of tack. A preferredionizing radiation is an electron beam having at least about a 1 MeV todeliver between about 1.5 and 2.5 megarads. Other sources of ionizingradiation such as 60CO or 137CS may be used for particular applications.The degree of cross-link has considerable effect on the degree of tack.If there is insufficient cross-linking, resultant PVP reservoir 114 doesnot retain shape, may detach from reinforcement 126 and is extremedifficult to handle. If the degree of crosslinking is too great, theresultant PVP reservoir 114 has insufficient tack to adhere to electrode112 or to patient contact area 122.

[0070] The use of the electron beam for cross-linking the PVP forreservoir 114 has a particular benefit to the present invention. Unlikegamma radiation that has a potential penetration of several feet ofconcrete, the electron beam penetration depth is described in the unitsof cm of water. This property of the electron beam can be utilized incontrolling the degree of cross-link in reservoir 114. The exposure canbe controlled so that there is a differential degree of tack on surface118 than on surface 120 of reservoir 30 114. The differential degree oftack on the first surface and the second surface may be preselected toallow a sufficient degree of tack on surface 120 to ensure asufficiently strong bond between electrode 112 and reservoir 114 tosubstantially prevent separation of the electrode and the reservoirwhile allowing the reservoir to be removed from the patient's skin.

[0071] The preferred degree of cross-link is determined by the degree oftack as described below. The preferred which results in a swelling ratioof greater than 3. Additionally, because the bibulous material isconstrained in the "x" and "y" directions by the reinforcement 126, bestseen in Fig. 6, the swelling that occurs upon imbibement of aqueoussolution, preferably occurs substantially only in the "z" direction,i.e., to increase the distance "d" between first surface 118 and secondsurface 120.

[0072] The manufacture of hydrophilic reservoir 114 is preferably begunwith a web of reinforcement 126 being coated on both sides with aviscous solution of the PVP with a concentration of between about twentypercent to about thirty percent, preferably about 24 percent, (w/w) inan aqueous solution. When prepared in this fashion, the preferred PVPsolution has a viscosity similar to that of molasses and is adherent toreinforcement 126. As the coating of PVP is applied, web 126, with thecoating is preferably sandwiched between two release liners. Preferably,one of the release liners 130 is formed from a stiff polymeric material,such as PET coated with polyethylene or silicone and the like. Stiffrelease liner 130 serves as an anvil for die cutting out sections ofhydrophilic reservoir 114 in the shape desired for incorporation intothe iontophoretic device electrode reservoir assembly. Once the PVP iscoated onto reinforcement 126 and placed between the release liners, theentire web, i.e., reinforcement 126, the PVP coating and the releaseliners, is exposed to the preselected dose of ionizing radiation forcross linking. Preferably, the thickness of the cross-linked material isbetween about 35 to about 45 mils. For particular applications, otherthickness may be preferred. Upon cross linking, the reinforced PVPreservoir material preferably has a cohesive strength, a tackinesssufficient to adhere releasably to a patient's skin and to form anadhesive bond 124 with conductive ink electrode 112 on a flexiblesubstrate 140. Preferably, the adhesive bond formed between reservoir114 and conductive ink electrode 112 is stronger that the cohesivestrength of the cross-linked PVP used to form the reservoir. This strongbond between electrode 112 and reservoir 114 ensures good electricalcontact and substantially prevents the reservoir from detaching from theelectrode. Additionally, it is also preferred that the strength ofadhesive bond 124 formed between the reservoir 114 and conductive inkelectrode 112 is stronger than an adhesive bond formed between thesurface of the patient's skin and reservoir 114 and that the cohesivestrength of the reservoir is greater than the strength of the adhesivebond between the patient's skin and the reservoir. This substantiallyensures that when reservoir 114 is removed from the patient's skin, thereservoir is substantially removed from the patient's skin, leavingsubstantially no residue.

[0073] In addition to the PVP in aqueous solution, preferably, thecoating solution may also include preservative materials to inhibitmicrobial growth such as para-benzoic acid (paraben) and the like. Asuitable preservative includes a series of mixed parabens including,methyl paraben, ethyl paraben, n-propyl paraben, iso-propyl paraben,n-butyl paraben and 2-phenoxyethanol and is sold under the tradename"Phenonip" by Nipa Laboratories, Wilm. DE. In the present invention, thematerial has been shown effective at substantially preventing microbialgrowth at a concentration of about one-percent in the 24% aqueous PVPsolution. A further benefit of the radiation cross-linking of the PVPwith preservative is that the radiation dose used for cross-linking issufficient to substantially eliminate most microorganisms and thepresence of the preservative then substantially inhibits and furthergrowth after loading and during shelf storage.

[0074] A preferred technique for measuring tack is called described inan ASTM method No.D3121-94 entitled: "TACK ROLLING BALL METHOD" (TRBM).This standardized test method utilizes a standard inclined trough thatdelivers a standard ball bearing onto the surface of the material beingtested. The ball is released from a standard height in the trough ontothe surface of the test material and a measurement is made of thedistance in mm that the ball rolls on the surface being tested. Thegreater the tack exhibited by the test material, the shorter thedistance the ball rolls. For the preferred cross-linked PVP used inreservoir 114, the TRBM values are preferably between about 15mm toabout 40mm. If the tack is substantially greater than the preferredvalue, reservoir 114 may lack cohesive strength and not be shaperetaining. If the tack is substantially less than the preferred value,there is insufficient adherence to the skin and to the electrode. Othermethods of measuring adhesive ability are also useful for characterizingthe preferred cross-linked PVP. These methods include the probe tack andpeel from steel. These tests are useful to characterize the cross-linkedhydrophilic polymeric material used to form reservoir 114. An empiricaldescription of the preferred material is that, when cut into discs ofthe a size about S square centimeters, the discs are sufficientlyadherent when loaded with the aqueous medicament to be lifted after agentle pressure with an index finger on the surface of the disc.

[0075] When cross-linked PVP as described above is used in aniontophoretic device of the invention, the PVP concentration ispreferably about twenty-four percent w/w and after imbibement of anaqueous solution of the desired medicament to be delivered, the PVPconcentration is about fifteen percent. Other reservoirs used iniontophoretic devices have significantly higher concentrations ofmaterials required as carriers. The reservoir of the invention in havingonly about fifteen percent PVP provides the an unexpected benefit to theart by allowing the reservoir to be physically smaller and to increasethe efficiency of the drug delivery by making the drug more availablefor delivery and to provide sufficient tack to both patient skin andelectrode to ensure substantially uniform electrical contact.

[0076] An example of a drug delivery system using the reservoir assemblyof the invention is prepared as follows. A solution ofpoly(vinylpyrolidone), (PVPK90-F BASF) at a concentration of 24% w/wcontaining 1 % w/w mixed parabens (Phenonip, Nipa Laboratories) in 0.06%sodium chloride was prepared. After thorough mixing the resultantviscous solution was coated onto both sides, best seen in Fig. 7, of areinforcement (Reemay 2004, spun bonded polyester to a thickness ofabout 40 thousandths of an inch (40mils). The coated reinforcement wasapplied to a release liner 132 formed form low density polyethylene(LDPE) film on one side and stiffer laminate 130 of 2mi1 polyester and2mil LDPE disposed so that the LDPE laminate was on the other side ofthe viscous solution. The material vas then exposed to electron beamirradiation with the LDPE film was closest to the source of the electronbeam energy. A dosage of about 2 megarad was administered to thematerial causing the PVP to crosslink. LDPE film 132 was then removedfrom one side of the PVP and the material was cut into the desired, bestseen in Figs. 6 and 8, five square centimeter shapes for the activeelectrode. The material with laminate release liner 132 remaining on theother side was bonded on exposed side 120 onto a flexible substratecoated with conductive ink electrode 112 containing silver and silverchloride in a suitable vehicle covering between about 60% to about 90 %of the surface are of substrate 140 in the region where reservoir 114 ispositioned, preferably about 90% of its surface with a loading of oneand one half to about five grams of ink per square centimeter of surfacearea. By keeping the coverage of the ink electrode below about 90%,direct contact between the patient's skin and the ink electrode issubstantially precluded. After cross-linked material 114 is bonded toflexible ink electrode 112, reservoir 114 is ready to be loaded with theaqueous drug solution.

[0077] Flexible ink electrode 112 containing silver and silver chlorideis applied to the flexible substrate to connect the power source to thereservoir 114. The ink preferably has a resistivity of less than about120 ohms per square. A suitable ink is available from E.I.du Pont deNemours, Wilm. DE. The terminology of "ohms per square" is developedfrom the thin film electrode art. A term "ohm-cm" is used to define thespecific resistance or resistivity of a material and is labeled by theGreek letter P (RHO). Since the metric system is the standard measuringused in laboratories, P is defined as the number for ohms resistancebetween parallel faces of a cubic centimeter of a material. Everymaterial has a specific conductivity, so P is different for eachmaterial. This term is also known as ohms per centimeter cubed. In thecase where the material is in the form of a thin (i.e., about 0.00025 cmto about 0.025 cm) the term is defined as ohms per square. This isdefined as the resistance of a square surface area of film and isindependent of the size of the square. In the first instance R=PL/A, inthe case of a film A=Wt, where t is the thickness of the film so thatnow R=PL/Wt, since L=W for any size square, this leads to R=P/t. As P isa constant for any given material, it is apparent that R variesinversely as the film thickness. As a consequence, when a resistance isspecified in ohms per square and the resistivity of the conductive inkor film is known, the effective film thickness is thus specified. In theinstant example, a preferred thickness is achieved with at loading ofbetween about one and one-half to about five grams of conductive ink persquare centimeter of surface for electrode 112 which provides aresistivity of less than about 120 ohms.

[0078] In the present example, an aqueous loading solution of 30%lidocaine HCI, 3% epinephrine, 30% glycerin, 0.05% sodium metabisulfite,0.03% ethylene diamine tetraacetic acid, and 0.06% citric acid are usedfor the loading solution. The medicaments for delivery are lidocaine HCIand epinephrine, the glycerin serves as a humectant, the other minorcomponents serve to enhance drug stability by chelating metal ions andserving as antioxidants. In order to load this solution onto thereservoir with electrode 112, laminate release liner 132 is removed fromside 118 of reservoir 114 and a three-hundred microliter aliquot of thisloading solution is applied to exposed surface 118, which is thencovered with a final cover that remains in place until the reservoir isapplied to a patient to protect the reservoir. Other aqueousformulations of other medicaments and other concentrations may beenvisioned for the electrode assembly of the invention and are to beconsidered within the scope of the invention. The electrode assembly 110of the invention when loaded with the aqueous medicament solutiondescribed above has demonstrated sufficient shelf stability when storedin a package formed from materials substantially resistant to thepassage of moisture and oxygen at accelerated, ambient and cycledtemperatures for two years.

[0079] A counter electrode assembly for the iontophoretic device of theinvention is formed by cutting a second shape from the cross-linked PVPwith a surface area of about 2.75 square centimeter area. A counterelectrode reservoir is assembled in the same fashion as the activeelectrode described above. This counter electrode reservoir ispreferably loaded with an aqueous solution containing about 30%glycerin, 1 % mixed parabens, 0.06% sodium chloride. The aqueous carrierfor both of the solutions preferably meets the standard for purifiedwater in the USP XXXIII.

[0080] It has been shown that if the loading solutions are not loadedsubstantially uniformly across surface 118 of reservoir 114, thatlocalized thickness variations of the reservoir may develop in thecross-linked PVP with adverse effects on attachment to electrode 112 andsubsequent attachment to the patient. Additionally, the localizedconcentration differentials of chloride ion may facilitate deteriorationof the silver/silver chloride electrode. Therefore, it is preferred thatthe loading solutions be substantially uniformly loaded across surface118 of the electrode reservoir. For the active electrode containing thelidocaine and epinephrine, a loading level of about three hundredmicroliters is preferred for a five square centimeter, forty-thousandthsthick reservoir with a uncharged volume of about 0.5cc resulting in acharged volume of about 0.8cc. For the counter or return electrode withan area of about two and three-quarters square centimeter surface area,the preferred loading is about two hundred microliters of the aqueoussolution.

[0081] When the cross-linked PVP material is loaded with the aqueouscharging solutions, the final PVP concentration of in the electrode isreduced from about twenty-four percent to about fifteen percent. Thecross-linked PVP swells to about one hundred-fifty percent of itsuncharged volume, and because of the reinforcement, the swelling occursprimarily in the "z" direction or increases the thickness of thereservoir 114 about sixty percent.

[0082] The reservoir electrode of the invention is an improvement to theart of iontophoretic electrode reservoirs. The reservoir is efficient inits utilization of available drug. Medicaments known to be labile, suchas epinephrine, have satisfactory shelf stability when incorporated intothe reservoir. Since the reservoir of the invention is flexible andadhesive, the reservoir electrode makes good uniform contact with thepatient's skin, minimizing any tendency for the current to concentrateat a particular point causing irritation or burns to the patient's skin.The reservoir electrode is easily prepared and its properties such asadhesion, size and medicament loading are easily adjustable duringmanufacture.

Claims
 1. An iontophoretic drug delivery device, comprising: a reservoirincluding epinephrine, wherein the iontophoretic drug delivery device isprepackaged as a ready to use device.
 2. The iontophoretic drug deliverydevice of claim 1, wherein the reservoir further comprises lidocaine. 3.An iontophoretic drug delivery device, comprising: an electrodeassembly, comprising: a working reservoir situated in electricallyconductive relation to the electrode assembly, wherein the workingreservoir comprises an aqueous swollen cross-linked water solublepolymer, lidocaine and epinephrine.
 4. The iontophoretic drug deliverydevice of claim 3, wherein the iontophoretic drug delivery device isprepackaged as a ready to use device.
 5. The iontophoretic drug deliverydevice of claim 3, wherein, as measured by weight % of the total weightof the working reservoir, epinephrine is present up to 0.1 wt. %.
 6. Theiontophoretic drug delivery device of claim 5, wherein the lidocaine ispresent up to 10 wt. %.
 7. The iontophoretic drug delivery device ofclaim 6, the working reservoir further comprises: glycerin, sodiummetabisulfite, and EDTA.
 8. The iontophoretic drug delivery device ofclaim 7, wherein the concentration of glycerin is up to 10 wt. %, theconcentration of sodium metabisulfite is up to 0.05 wt. %, theconcentration of EDTA is up to 0.01 wt. %.
 9. The iontophoretic drugdelivery device of claim 6, wherein the iontophoretic drug deliverydevice is prepackaged as a ready to use device.
 10. The iontophoreticdrug delivery device of claim 3, wherein the concentration ofepinephrine, as measured in weight % of the total weight of thereservoir, is about 0.1 wt. % and the concentration of lidocaine isabout 10 wt. %.
 11. The iontophoretic drug delivery device of claim 10,the working electrode further comprises about 10 wt. % glycerin, about0.05 wt. % sodium metabisulfite, and about 0.01 wt. % EDTA disodium. 12.The iontophoretic drug delivery device of claim 3, wherein the electrodeassembly further comprises from one to three return electrodes and aworking electrode.
 13. The iontophoretic drug delivery device of claim12, wherein the one to three return electrodes have a total surface areabetween 1 to 5 cm² and wherein the working electrode has a surface areabetween 2 to 10 cm².
 14. The iontophoretic drug delivery device of claim3, wherein the working reservoir further comprises at least onestabilizer.
 15. The iontophoretic drug delivery device of claim 14,wherein at least one stabilizer is at least one of sodium metabisulphiteand EDTA.
 16. The iontophoretic drug delivery device of claim 14,wherein the working reservoir further comprises at least one additive.17. The iontophoretic drug delivery device of claim 16, wherein theadditive is selected from glycerin, propylene glycol, polyethyleneglycol, and conductive salts.
 18. The iontophoretic drug delivery deviceof claim 3, wherein the aqueous swollen cross linked water solublepolymer acts as an adhesive.
 19. The iontophoretic drug delivery deviceof claim 18, wherein the aqueous swollen cross linked water solublepolymer is selected from polyethylene oxide, polyvinyl pyrrolidone,polyvinyl alcohol, and polyacrylimide.
 20. An iontophoretic drugdelivery device, comprising: an electrode assembly, comprising: areservoir situated in electrically conductive relation to the electrodeassembly, wherein the reservoir comprises an aqueous swollen high energyirradiation cross-linked water soluble polymer.
 21. The iontophoreticdrug delivery device of claim 20, wherein the aqueous swollen highenergy irradiation cross-linked water soluble polymer is crosslinked byexposure to electron beam irradiation or gamma irradiation.
 22. Theiontophoretic drug delivery device of claim 20, wherein the reservoirfurther comprises the at least one medicament.
 23. The iontophoreticdrug delivery device of claim 21, wherein the aqueous swollen highenergy irradiation cross linked water soluble polymer is selected frompolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, andpolyacrylimide.
 24. A method of making a reservoir for an iontophoreticdrug delivery device, comprising: coating a reinforcing member with aviscous water soluble polymer solution; and cross linking the viscouswater soluble polymer solution by high energy irradiation.
 25. Themethod of claim 24, wherein coating a reinforcing member comprises:applying a portion of the viscous water soluble polymer solution to oneside of the reinforcing member; applying a second portion of the viscouswater soluble polymer solution to one side of a release liner; andlaminating the release liner and the reinforcing member together suchthat both surfaces of the reinforcing member are coated with the viscouswater soluble polymer solution.
 26. The method of claim 25, wherein theviscous water soluble polymer solution is applied to the reinforcingmember and the release liner to a thickness of about 5 mil to 30 mil.27. The method of claim 25, wherein coating a reinforcing member furthercomprises: applying a final release liner to the viscous solutionapplied to the reinforcing member to form a laminate.
 28. The method ofclaim 27, wherein the final release liner is an electrode.
 29. Themethod of claim 27, further comprising replacing one of the releaseliner and the final release liner with an electrode in flexible sheetform.
 30. The method of claim 25, further comprising adding at least onemedicament to the reservoir.
 31. The method of claim 30, wherein the atleast one medicament comprises lidocaine and the method furthercomprises adding a vasoconstrictor, stabilizers and glycerin to thereservoir.
 32. The method of claim 27, further comprising cutting thelaminate to form the reservoir.
 33. An iontophoretic drug deliverydevice, comprising: a single electrode assembly, comprising: a workingelectrode connected to a working reservoir, the working reservoircomprising lidocaine and epinephrine; and a return electrode connectedto a return reservoir, the return reservoir comprising an electrolyte;wherein the working reservoir and the return reservoir independentlycomprise at least one crosslinked water soluble polymer selected frompolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, andpolyacrylimide; and wherein the electrode assembly is prepackaged as aready to use device.
 34. The iontophoretic drug delivery device of claim33, wherein the working reservoir and the return reservoir comprise thesame crosslinked water soluble polymer.
 35. The iontophoretic drugdelivery device of claim 33, wherein, as measured by weight % of thetotal weight of the reservoir, epinephrine is present up to 0.1 wt. %.36. The iontophoretic drug delivery device of claim 35, wherein thelidocaine is present up to 10 wt. % based on the total weight of thereservoir.
 37. The iontophoretic drug delivery device of claim 36,further comprising: glycerin, sodium metabisulfite, and EDTA.
 38. Theiontophoretic drug delivery device of claim 37, wherein theconcentration of glycerin is up to 10 wt. %, the concentration of sodiummetabisulfite is up to 0.05 wt. %, the concentration of EDTA is up to0.01 wt. %, all based on the total weight of the reservoir.
 39. Theiontophoretic drug delivery device of claim 33 wherein the concentrationof epinephrine, as measured in weight % of the total weight of thereservoir, is about 0.1 wt. % and the concentration of lidocaine isabout 10 wt. %, all based on the total weight of the reservoir.
 40. Theiontophoretic drug delivery device of claim 39, further comprising about10 wt. % glycerin, about 0.05 wt. % sodium metabisulfite, and about 0.01wt. % EDTA disodium.
 41. The iontophoretic drug delivery device of claim33, further comprising from one to three return electrodes.
 42. Theiontophoretic drug delivery device of claim 41, wherein the returnelectrodes have a total surface area from 1 to 5 cm² and wherein theworking electrode has a surface area from 2 to 10 cm².
 43. Theiontophoretic drug delivery device of claim 33, wherein the workingreservoir further comprises at least one stabilizer.
 44. Theiontophoretic drug delivery device of claim 43, wherein at least onestabilizer is at least one of sodium metabisulphite and EDTA.
 45. Theiontophoretic drug delivery device of claim 43, wherein the workingreservoir further comprises at least one additive.
 46. The iontophoreticdrug delivery device of claim 45, wherein the additive is selected fromglycerin, propylene glycol, polyethylene glycol, and conductive salts.47. The iontophoretic drug delivery device of claim 33, wherein theaqueous swollen cross linked water soluble polymer acts as an adhesive.48. An iontophoretic drug delivery device, comprising: an electrodeassembly, comprising: a working reservoir situated in electricallyconductive relation to the electrode assembly, wherein the workingreservoir comprises an aqueous swollen cross-linked water solublepolymer, lidocaine and epinephrine; wherein the iontophoretic drugdelivery device is prepackaged as a ready to use device.